IE48935B1 - Antiinflammatory 4,5-diaryl-2-nitroimidazoles,method for their preparation and pharmaceutical composition containing them - Google Patents
Antiinflammatory 4,5-diaryl-2-nitroimidazoles,method for their preparation and pharmaceutical composition containing themInfo
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- IE48935B1 IE48935B1 IE1643/79A IE164379A IE48935B1 IE 48935 B1 IE48935 B1 IE 48935B1 IE 1643/79 A IE1643/79 A IE 1643/79A IE 164379 A IE164379 A IE 164379A IE 48935 B1 IE48935 B1 IE 48935B1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/46—Oxygen atoms
- C07D213/50—Ketonic radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/91—Nitro radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
- C07D333/22—Radicals substituted by doubly bound hetero atoms, or by two hetero atoms other than halogen singly bound to the same carbon atom
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Abstract
The new compounds of the formula …… where… R1 and R2 independently are …… with the proviso at least one of R1 and R2 must be …… Y1 is F, Cl N(CH3)2 or C1-C4 alkoxy;… Y2 is H, F, Cl;… R3 is H, …… 2-tetrahydropyranyl, 2-tetrahydrofuranyl, …… R6 is C1-C3 alkyl, benzyl, -CH2CH2OCH3 or …… R7 is C1-C4 alkyl or benzyl; and Ar is …… where… Y3 is H, F, Cl, Br, C1-C4 alkyl, C1-C4 alkoxy or nitro;… e.g. 4,5-bis(4-fluorophenyl)-2-nitroimidazole; or their pharmaceutical suitable salts have antiinflammatory activity. A method for preparation of these compounds, involving nitration of 4,5-disubstituted-1-(substituted) imidazoles in 2-position, is given.
Description
This invention relates to antiinflammatory imidazoles.
Lombardino, in U.S. Patent 3,707,475 discloses antiinflammatory 4,5-diaryl-2-substituted imidzoles.
Doebel, in U.S. Patents 3,505,350 and 3,651 ,080, respectively, 5, discloses antiinflammatory 4-alkyl-5-aryl-1-substituted
-2-mercaptoimidazoles and 4-alkyl-2-alkylthio-5-aryl -1-substituted imidzoles.
Zauer, K. , et al . , in (hem. Ber., 106, 1638 (1973) disclose 4,5-Ka(4-methoxyphenyl)-2-methylthioimidazole and 4,5]0. bis (4-chlorophenyl)-2-methylthioimidazole but do not suggest any use.
A number of references such as Current Sai. India,
17, 184—85 (1948) and Aota. (hem. Aead. Sci. Bung., (2) 197—212 (1973) disclose 2-(substituted-thio)15, 4,5-diphenylimidazoles with substituents such as methyl, propyl, allyl, and acetonyl.
4893S
-3There is a continuing need for safe and effective antiinflammatory agents. Inflammation is a disease process characterized by redness, fever, swelling, and pain.
Arthritis, in its various forms, is the most prevalent,
. chronic, and severe of the inflammatory diseases.
Traumatic injury and infection also involve inflammation, and antiinflammatory drugs are often used in their treatment. The usefulness of most commercial antiinflammatories is limited because of toxicity and adverse side-effects.
. Many produce gastric irritation and other effects, such as changes in blood cells and central nervous system. Adreno-cortical steroids produce gastric irritation and suppression of normal adrenal function.
The present invention results from efforts to develop
. newanti-arthritic compounds with good antiinflammatory activity and minimal side effects that could be more effective in treating arthritis than presently available drugs.
In addition to antiinflammatory properties, some compounds
. of this invention have demonstrated analgesic activity in a test procedure. This additional property is desirable in treatment of arthritis or related diseases; however, such compounds can be employed solely to alleviate pain.
-4According to this invention there is provided compounds of formula 1, pharmaceutical compositions containing them and methods of using them to treat arthritis in mammals.
CD
. where
R1 and R2 independently are
with the proviso at least one of R^ and R2 must be
4893S
Υ·| is F, Cl, N(CH3)2 or C-,—C4 alkoxy; Y2 is H, F, Cl;
R, is H, -CHORc, 2-Tetrahydropyranyl,
I '5
0 0
II
-CORy, -CRy, -CAr, or
Rg is H or methyl;
Rg is Cq—C3 alkyl, benzyl, —CHgCf^OCHg is Cq—C4 alkyl or benzyl; and
-tetrahydrofuranyl,
-S02Ar;
II or -CRy;
Ar is
-6where
Y3 is H, F, Ci, Br, C-j—alkyl, Cq—alkoxy or nitro; or its pharmaceutically suitable acid addition salt where at least one of Rq and R2 is 3-pyridyl, or
where
Yq is N(CH3)2;
or its pharmaceutically suitable metal salt where R3 is H.
Some of the compounds of formula 1 have analgetic activity 10· in addition to antiinflammatory activity.
Pharmaceutical salts
Pharmaceutically suitable acid addition salts of compounds where one of Rq and Rg is 3-pyridyl and/or
where
Y1 is N(CH3)2 include those made with physiologically acceptable acids and such salts include hydrochloride,
, sulfate, phosphate and nitrate.
Pharmaceutically suitable metal salts where R3 is H include those of certain metals, such as sodium, potassium, and calcium.
Preferred Compounds
. Compounds preferred for antiinflammatory activity are those where; independently: a) Rj and R2 are independently
and more preferably
or
b) where either R^ or Rg is
. Y is F, Cl, or OCHg, and more preferably this constituent is in the para-position; and Yg is H; or c) Rg is H.
Examples of suitable compounds are where R-| and Rg are both
F and Rg is H; and
R-| and Rg are both
.
OCHg and Rg is H.
Synthesis.
Compounds of formula 1 can be prepared by first reacting
. a 4,5-disubstituted imidazole (11) with an appropriate reagent such as benzyl chloromethyl ether, 2-chlorotetrahydrofuran, dihydropyran, benzenesulfonyl chloride, or ethyl vinyl ether (Equation A). The resulting 4,5disubstituted-1- (substituted)imidazole (111) is then
. reacted with a strong base, such as n-butyl lithium, followed by dinitrogen tetroxide or some other suitable nitrating agent, such as acetyl nitrate or alkyl nitrates (Equation B). Optionally, the choice of the protecting group and the workup conditions allows isolation of a desired 4,5-disubstituted-2-nitroimidazole (1, Rg = H) di rectly.
I (R3 = H) (R3 t H)
-ΠAlternatively, the Rj-substituent other than hydrogen of formula 1 can be introduced by direct alkylation, acylation or sulfonylation of the compounds of formula 1 where R3=H(Equation C). This reaction can be carried out in
. the absence of presence of a base, such as potassium carbonate, pyridine, triethylamine, potassium t-butoxide, methyllithium or the like. The reaction can be run neat, using the reagent as solvent, or in the presence of an inert solvent, including but not limited to dimethylformamide,
. glyme, THF, pyridine, methylene chloride. The temperature of the reaction can be in the range -78°C to the boiling point of the solvent or reagent, if used in excess as the solvent. Examples of alkylating, acylating and sulfonylating agents that can be employed are alkoxymethyl
. halides, such as benzyloxymethyl chloride; acyloxymethyl halides, such as chloromethylpivalate; dihydropyran; 2-chlorotetrahydrofuran; alkyl chloroformates, such as ethyl chloroformate; alkanoic anhydrides and alkanoyl halides, such as acetic anhydride; aroyl halides, such
. as benzoyl chloride; and arylsulfonyl halides, such as benzene-sulfonyl chloride.
The 4,5-disubstituted imidazoles of formula 11 are commercially available or may be prepared by techniques well known to those skilled in the art, e.g. H. Bredereck,
-12et al., Ber., 86,88 (1953) and Ber., 92, 338 (1959).
Preparation of pharmaceutically suitable salts of formula 1 can be in accordance with well-known techniques of forming salts.
. The preparation of these compounds is further illustrated by the following Examples. Parts are by weight and temperatues are in degrees centigrade unless otherwise stated.
EXAMPLE 1
. 4,5-bis(4-fluorophenyl)-2-nitroimidazole
A mixture of 124 g (0.484 mole) of 4,5-bis(4-f1uorophenyl) imidazole, 84 g (1.0 mole) dihydropyran, 20 g boron trifluoride etherate and 1 g ethyl acetate was heated at reflux over a weekend. Analysis by TLC (ethyl acetate)
. showed the presence of some unchanged starting material, so 20 g (-0.24 mole) of dihydropyran and 5 g boron trifluoride etherate was added and heating was continued overnight. The mixture was then diluted with 1 I ether and washed with 10% sodium bicarbonate solution (3x11).
. The organic layer was dried and concentrated on a rotary
-13evaporator. The residual solid was reerystallized from methylcyclohexane (removing some insoluble starting material by filtration) to give 140,2 (85%) of
4,5-bi s(4-fluoropheny!)-l-(2-tetrahydropyranyl) imidazole
. as a white solid, mp 149—152°. F—NMR indicated purity -95%. A smaller run was chromatographed to give pure material mp 158—9°. IR: 3.25 μ (=CH); 3.38, 3.49, (sat. CH); 6.22, 6.28, 6.41, 6.60, 6.69 p(C=C and/or C=N);
8.20 μ (CF); 9 μ region ( C—0—C). H—NMR; m(1.4—2.1
. δ, 6H); m (3.45, 1H); m (4.0 5, 1H); m (4.7 δ,ΙΗ); m (6.6-7.5 δ, 8H); s (7.8 δ, 1H), F—NMR: two multiplets (112.4 5 and 116.5 δ, each decouples to a singlet).
To a mixture of 17.0 g (50 mmole) of 4,5-bis(4-fluorophenyl) -l-(2-tetrahydropyranyl)imidazole, 6.4 g (55 mmole) of
. Ν,Ν,Ν1,Ν'-tetramethylenediamine and 200 ml of ether cooled to -78° was added dropwise 35 ml (55 mmole) of 1.6M butyl lithium. After stirring for 15 minutes, a solution of 7.9 g (86 mmole) of dinitrogen tetroxide in 50 ml of ether was added dropwise. The reaction mixture was allowed
. to warm to room temperature and then was distributed between 5% aqueous sodium bicarbonate and ether. The ether was dried and evaporated to give 21.7 g of an amber oil.
-14The oil v/as heated with a mixture of 125 ml of ethanol and 10 ml of IN aqueous hydrochloric acid for a few minutes. The reaction mixture was concentrated under vacuum.
. Chromatography and recrystallization of the product from toluene gave 6.1 g of 4,5-bis(4-fluorophenyl)-2nitroimidazole, m.p. 245—5° (dec.). The infrared,
NMR and F—NMR spectra were consistent with the assigned structure.
. Anal calc'd. for CqgHgFgN^Og1
C, 59.81; H.3.01; N.13.95.
found:C, 60.21; H.3.03; N.13.55.
EXAMPLE 2
4,5-bis(4-Methoxyphenyl)-2-nitroimidazole
. By the procedure described in the first paragraph of Example 1, 4,5-bis(4-methoxyphenyl)imidazole was converted in 50% yield to 4,5-bis(4-methoxyphenyl)-1-(2-tetrahydropyranyl) imidazole, as a white solid, m.p. 123—5°. IR: 3.26 μ (=CK); 3.40, 3.53 μ (sat. CH); 6.17, 6.32, 6.58, 6.68 μ
48835
-15(C=C and/or C=N); 8.03 μ (aryl-o); 9.60 and 9.72 μ (C—0—C). H—NMR: m (1.3—2.1 6, 6H); two singlets
(3.75—3.85 δ, 6H); m (3.2-4.2 δ, 2H); -(4.85 δ, 1H); two A2B2 quartets (6.7—7.6 δ . SH); s (7 .85 δ, 1H). Anal. Calc'd for C22H24N2°3: C, 75.21; H.6.64; N.7.69. Found:C, 72.32; H.6.35; N,7.37. By the procedure described in Example 1, 14.5 g of 4,5-bis
(4-methoxyphenyl)-l-(2-tetrahydropyranyl)imidazole was
. converted to 4,5-bis(4-methoxyphenyl)-2-nitroimidazole.
Chromatography gave an analytical sample, m.p. 174° (dec.). The infrared and NMR spectra were consistent with the assigned structure.
Mass Calc'd for 325. 1062.
. Mass found: 325. 1030.
EXAMPLE 3
4-(4-fluorophenyl)-5-(2-thi enyl)-2-ni troimidazole
To a mixture of 100.0 g. (0.65 mole) of 4-fluorophenylacetic acid and 260.0 g of thiophene warmed to 40°C was added
. dropwise 150.0 g (0.71 mole) of trifluoroacetic anhydride.
The reaction mixture was heated at reflux for 3 hours,
- 48935
-16cooled and then poured into ice. The aqueous layer was made basic with sodium carbonate and the product was extracted into ether. The combined ether extracts were washed with water and, after drying over anhydrous
. potassium carbonate, were evaporated to give 150.5 g of an oil. Crystal!ization from methanol afforded 94.1 g of 2-(4-fluorophenyl)-1-( 2-thienyl)ethanope, m.p.
60—61°C. ..
Anal. Calc'd for C^2 Hg FOS:
C, 65.45; H.4.09;
found:C, 65.45 H,4.06
To a solution of 94.1 g (0.43 mole) of 2-(4-fluorophenyl)
-1-(2-thienyl)ethanone in 700 ml of ether was added dropwise a solution of 65.0 g. (0.41 mole) of bromine
. in 140 ml. of methylene chloride at room temperature with stirring. The solvent was removed under vacuum to give 125.0 g of 2-bromo-2-(4-fluorophenyl)-1-(2thienyl)ethanone.
A mixture of the 2-bromo-2-(4-fluorophenyl)-]-(2-thienyl)
. ethanone and 465 ml of formamide was heated at reflux under an air condenser for 2 hours. The reaction mixture was allowed to cool to room temperature and 73,3 g pf 4-(4-fluorophenyl)-5-(2-thienylJimidazole, m.p. 182—189°C,
-17collected by filtration. An analytical sample was prepared by recrystallization from nitromethane, m.p.
200—202°C. H—NMR: m (6.9-7.7 6.7H); s (7.8 δ, 1H).
Anal. Calc'd for C-jgHgNgFS:
· C 63.93, H.3.69 N.11.48.
found:C 63.43, H.3.82; Ν,Π.56.
By the procedure described in the first paragraph of Example 1, 35.0 g of 4-(4-fluorophenyl)-5-(2-thienyl)imidazole was converted to 56.6 g of 4 (5)-(4-fluorophenyl)-5(4)-(2-1hieny1)
. l-(2-tetrahydropyranyl)imidazole. Chromatography on neutral alumina (Woelm activity Grade 1) eluting with chloroform gave 30.0 g of pure material as a mixture of two isomers. H—NMR:m (1.4—2.1 6,6H);m (3.3 6,lH);m(4.0 δ,ΙΗ); m(4.8 δ,ΙΗ) ;m(6.7—7.7δ,7Η); 2s(7.9, 1H).
· By the procedure described in Example 1, 30.0 g of 4(5)(4-fluorophenyl)-5(4)-(2-thienyl)-1-(2-tetrahydropyranyl) imidazole was converted to 4-(4-fluorophenyl)-5-(2-thienyl)2-nitroimidazole. Purification was effected by dissolving the crude product in aqueous 0.2 M potassium hydroxide
. followed by filtration, then acidification with acetic acid to precipitate an analytical sample, mp. 177.5—179°C.
The infrared and NMR spectra were consistent with the assigned structure.
-18Mass Calc'd for C^gHgFNgOgS: 289; Mass found: 289.
Anal. Calc'd. for C^HgFNgOgS;
C, 53.98; H.2.77; N.14.53.
Found:C, 54.5; H.2.84; N.14.4.
EXAMPLE 4
. 4-(4-Ethoxyphenyl)-5-(4-fluorophenyl)-2-nitroimidazole.
A mixture of 24.4 g (86.5 mmoles) of 4-(4-ethoxyphenyl)-5(4-fluorophenyl)imidazole, 12.5 g (0.173 mole) of ethyl vinyl ether and 11.2 g (86.8 mmoles) of dichloroacetic acid in 175 ml. of toluene was heated at reflux for several
. hours. After cooling to room temperature, the reaction mixture was stirred overnight with 85 ml. of 20% aqueous sodium hydroxide. The toluene layer was separated, washed several times with water, dried over anhydrous potassium carbonate and then evaporated to give 21.6 g of 4(5)-(415. ethoxyphenyl )-5(4)-(4-fluorophenyl)-1-(1-ethoxyethyl) imidazole as an oil. The oil was chromatographed on neutral alumina (Woelm activity Grade 1) eluting with chloroform to give 18.0 g of pure material. H—NMR: m (1.0—1.8 6,
9H); q (3.2 6.2H); q (4.1 6,2H); q (5.1 6.1H); m (6.7-7.7
. 5.8H); s(7.8 6.1H).
By the procedure described in Example 1, 8.5 g of 4(5)-(4ethoxyphenyl)-5(4)-(4-fluorophenyl )-1 -(1-ethoxyethyl) imidazole was converted to 4-(4-ethoxyphenyl)-548935
-19(4-fluorophenyl)-2-nitroimidazole. The infrared and NMR spectra were consistent with the assigned structure. Chromatography on Silica-Ar with chloroform followed by recrystallization from 1-chlorobutane gave an
. analytical sample, mp 176°C (dec.).
Mass Calc'd for Cq yHq^N-jFOg: 327; Mass found; 327.
Anal Calc'd for CqyHq4N.3FO3:
C, 62.39; H.4.28; N.12.84.
Found:C, 62.4; H.4.33; N.12.6.
. EXAMPLE 5
4-(3,4-Dichlorophenyl)-5-phenyl-2-nitroimidazole.
A mixture of 4-(3-,-4-dichlorophenyl )-5-phenylimidazole (14.5 g, 50 mmole), ethyl vinyl ether (10 ml., 100 mmole) and dichloroacetic acid (4.2 ml., 50 mmole) in
. 100 ml toluene was heated at reflux under N2 for 1 hour. The cooled reaction mixture was treated with 50 ml. 20% aqueous NaOH, stirred overnight and then left to stand at room temperature for two days. The organic phase was washed with water, dried over KgCOg and
. concentrated on a rotary evaporator to give 4(5)(3,4-dichlorophenyl )-5(4)-phenyl 1-(1-ethoxyethyl)imidazole as an oil.
-20H—NMR 1.13 6 (t, J=7Hz,3H), 1.63 δ (d, J=6Hz,3H),
3.3 δ (2q, J=7Hz,2H), 5.13 δ (q, J=6Hz,lH), 7.28—7.8 6 (m, 8H), 7.91 δ (s, 1H).
The resultant (5)-4-(3,4-dichiorophenyl)-5-(4)-phenyl-1 5. (1-ethoxyethyl)imidazole (50 mmole) and Ν,Ν,Ν',Ν1tetramethylethylenediamine (7.5 ml., 55 molp) in 200 ml.
THF was cooled to -78°C under N2 and treated dpppwise with 1.6 M n-butylithium (41 ml. 65 mmole). After stirring for 15 minutes, a solution of dinitrogen tetroxide (7 ml.,
. HO mmole) in 25 ml. ether was added dropwise,- The reaction mixture was stirred for 1 hour at —78°C and then allowed to warm to room temperature. The dark mixture was poued into 300 ml. saturated aqueous NaHCO^ and extracted with ether. The combined organic extracts were washed
. with brine, dried and divided into two portions (3:1).
The larger portion was concentrated on the rotary evaporator, redissolved in 125 ml. ethanol, treated with 30 ml II and heated at reflux for 10 minutes. The reaction mixture was cooled to room temperature and diluted with 35 ml. water.
. The crystals were collected, washed with 0.1N KOH and recrystal 1ized from methylene chloride to give 1.2 g of 4-(3,4-dichlorophenyl)-5-phenyl-2-nitrpimidazole, mp.
248—249°C (D). Infrared and H—NMR spectra were consistent with the assigned structure. MS 333 (M+).
-21Anal. Calc'd. for C-j gligNgOgCl 2:
C, 53.91, H.2.71; N, 12.58;
Found:C, 53.86; H.2.54; N, 12.67.
EXAMPLE 6
. 4-(4-fluorophenyl)-5-(3-pyridyl)-2-nitroimidazole.
A mixture of 82.0 g (0.6 mole) of methyl nicotinate and 81.0 g (0.6 mole) of p-fluorobenzyl cyanide was added dropwise to a solution of 0.9 mole of sodium ethoxide in 250 ml. of ethanol at room temperature with stirring.
. The reaction mixture was heated at reflux overnight, cooled and then poured onto ice-water. The aqueous solution was washed with ether and then acidified with concentrated hydrochloric acid.A precipitate was collected by filtration and washed with water. A mixture of the
. solid with 350 ml. of 48% hydrobromic acid was heated at reflux overnight with stirring. The reaction solution was allowed to cool to room temperature and crystals were collected by filtration. The crystals were suspended in water which was then made basic with concentrated
. ammonium hydroxide. The product was extracted into ether, which, after drying over anhydrous potassium carbonate, was evaporated to afford 77.9 g of fluorobenzyl 3-pyridyl ketone as colorless crystals, mp. 64—65°C. IR: 6.0 m
-22(C=0). H—NMR: s{4.3 6,2H); m(6.9—7.6 δ,5Η); d/t (8.2,1H); d/d (8.8 δ,ΙΗ); d(9.3 δ,ΙΗ).
To a solution of 15.0 g (69.8 mmoles), 4-fluorobenzyl 3-pyridyl ketone in 120 ml. of acetic acid was added
. dropwise a solution of 12.3 g (76.9 mmoles) of bromine in 120 ml. of acetic acid at room temperature with stirring. After stirring overnight, a precipitate of 18.4 g of a-bromo-4-f1uorobenzyl 3-pyridyl ketone hydrobromide was collected by filtration.
. A mixture of the α-bromo 4-f1uorobenzyl 3-pyridyl ketone hydrobromide with 150 ml. of formamide was heated at reflux with an air condenser under nitrogen for 2 hours. The reaction mixture was allowed to cool to room temperature and then poured onto water. The aqueous solution was made
15_ basic with sodium carbonate and the product extracted into ether. The combined ether extracts were washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous potassium carbonate and evaporated to give
7,5 g of 4-(4-fluorophenyl)-5-(3-pyridyl)imidazole. The
. product was purified by chromatography on neutral alumina (Woelm activity Grade 1) eluting with ethyl acetate/ tetrahydrofuran mixtures and then crystallization with ether gave 2.2 g of pure imidazole, mp. 154—156°C. H—NMR;
-23m(6.8—7.58 δ,5Η); s(7.6 δ,ΙΗ); d/t (7.8 δ,ΙΗ); d/d (8.4 δ,ΙΗ); d(8.7 δ,ΙΗ).
Anal. Calc'd for C^H^gFNg:
C, 70.29; H.4.18; N.17.57.
. Found:C, 70.3; H.4.43; N,18.0.
Alternatively, a mixture of 28.8 g of a-bromo-4-fluorobenzyl 3-pyridyl ketone hydrobromide and 40.0 g of potassium acetate in 50 ml of acetic anhydride was stirred overnight at room temperature. The reaction mixture was poured into water
, and the product extracted into ether. The combined ether layers were washed with water and then 102 aqueous sodium bicarbonate solution. The ether layer was dried over potassium carbonate and evaporated. A solution of the residue in 250 ml. of IN aqueous hydrochloric acid was heated at
, reflux for 30 minutes, and after cooling, made basic with solid sodium carbonate. The product was extracted into ether and the combined ether extracts evaporated, after drying over anhydrous potassium carbonate, to give 16.5 g of α-hydroxy 4-fluorobenzyl3-pyridyl ketone.
. The 16.5 g of a-hydroxy 4-fluorobenzyl3-pyridyl ketone was reacted with 12.5 g of ammonium thiocyanate in 1propanol heated at reflux to give 11.3 g of 4-(4-fluorophenyl)
-(3-pyridyl)-1H-2-imidazolethiol, mp. 335—338° (dec.).
-244-(4-f1uorophenyl)-5-(3-pyridyl)1H-2-imidazolethiol (8.2 g) was added portionwise to a mixture of 30 ml. of 35% nitric acid at room temperature. After stirring overnight, the reaction mixture was diluted with water and made basic
. with sodium carbonate. The product was extracted into ethyl acetate, which, after drying over potassium carbonate was evaporated to yield 5.3 g of 4-(4-fluorophenyl)-5(3-pyridyl)imidazole.
8y the procedure described in the first paragraph of Example
. 4, 1.5 g of 4-(4-fluorophenyl)-5(3-pyridyl)imidazole was converted to 4(5)-(4-fluorophenyl)-5(4) (3-pyridyl)-l(1-ethoxyethyl)imidazole. Chromatography on neutral alumina (Woelm activity Grade 1) eluting with tetrahydrofuran gave pure material. H—NMR: t(1.2 δ,3Η); d (1.5 δ,3Η); m
. (3.0-3.4 δ,2Η); q (5.1 δ,ΙΗ); M (6.8-7.5 6,5H); t (7.7 δ, 1H); s (7.8 δ,ΙΗ); d/d (8.4 δ,ΙΗ); d(8.7, 1H).
By the procedure described in Example 1, 1.0 g of 4(5)-(4f1uorophenyl)-5(4) (3-pyridyl)-(1-ethoxyethyl)imidazole was converted to 4-(4-fluorophenyl)-5-(3-pyridyl-220. nitroimidazole. Rf = 0.19 TLC; silica gel G; ethyl acetate; methanol (90:10)
48835
-25-EXAMPLE 7
1-Benzoyl-4,5-bis(4-methoxyphenyl)-2-nitroimidazole.
To a solution of 4,5-bis(4-methoxyphenyl)-2-nitroimidazole (3 g, 9.2 mmole) and triethylamine (3.9 ml., 27.6 mmole) in 30 ml. THF at 0°C under N2 was dropwise added a solution
. of benzoyl chloride (1.2 ml., 10.1 mmole) in 5 ml THF.
The reaction mixture was stirred for 8 hours at 0°C and then left in the refrigerator overnight. The reaction was then diluted with 30 ml ether and filtered. The filtrate was concentrated on a rotary evaporator and chromatographed
. on Florisil. Recrystallization from methyl cyclohexane gave 1.89 g of 1-benzoyl-4,5-bis(4-methoxyphenyl)-2nitroimidazole, mp. 161—163°C.
IR: 1745 cm-1,H—NMR: 3.73 δ (s, 3H), 3.75 δ (s,3H), 6.67—7.83 δ (m, 13H), MS 429 (M+)
. Anal Calc'd. for Cg^H^gNgOg:
C, 67.12; H.4.46; N.9.7;
Found:C, 67.2; H.4.40; N.9.5.
489 35
- 26 EXAMPLE 8
1-Ethoxycarbonyl 4,5-bis(4-methoxyphenyl)-2-nitroimidazo!e.
To a solution of 4,5-bis(4-methoxyphenyl)-2-nitroimidazole (1.5 g, 4.6 mmole) in 25 ml pyridine at 0°C under 5 nitrogen was dropwise added ethyl chloroformate (1.5 ml.
156 mmole). After 5 hours at 0°C, the reaction mixture was diluted with ethyl acetate, washed 3 x IN HCl, 3 x saturated NaHC03, 1 x brine, dried and concentrated on a rotary evaporator. Chromatography on Florsil gave
487 mg. of 1-ethoxy-carbonyl -4,5-bis(4-methoxyphenyl)-2nitroimidazole as an oil. IR 1795 cm\H—NMR: 1.21 6 (t, J = 7Hz,3H), 3.7 6(s,3H, 3.8
6.6—7.76 δ (2 AB quartets, J=8Hz, 8H); MS 397 (M+).
EXAMPLE 9
1 - Acetyl-4,5-bi s(4-methoxyphenyl)-2-nitroimidazole.
To a solution of 4,5-bis(4-methoxyphenyl)-2-nitroimidazole (3,0 g, 9,22 mmole) and triethyiamine (7 ml., 51 mmole) in 30 ml. THF at 0°C under Ng was dropwise added a solution of acetyl chloride (1.3 ml., 18.4 mmole) in 5 ml. THF.
After 2 hours at 0°C, the reaction mixture was diluted with ethyl acetate washed with IN HCl, saturated aqueous
NaHC03 and brine, dried and concentrated on a rotary
48035
-27evaporator. Crystallization from ether gave approximately 600 mg. of starting material. HPLC of the mother liquor and crystal!ization from ether gave 1-acetyl 4,5-bis (4-methoxyphenyl)-2-nitroimidazo1e, mp. 146—151°C,
. H—NMR indicates purity >95%. H—NMR: 2.41 5 (s,3H),
3.8 δ (s, 3H), 6.73—7.56 δ (2AB quartets, J=9Hz, 8H).
EXAMPLE 10
1-(1-Ethoxyethyl )-4,5-bis(4-methoxyphenyl)-2-nitroimidazole.
A mixture of 4,5-bis(4-methoxyphenyl)-2-nitroimidazole
. ( lg. 308 mmole), ethylvinyl ether (1 ml. 6.16 mmole) and dichloroacetic acid (0.3 ml, 3.03 mmole) in 10 ml. toluene was heated at reflux under N2 for 1 hour. The reaction mixture was cooled , 2 ml. ethyl vinyl ether added and heating continued overnight. The cooled reaction mixture was treated
. with 5 ml. 20% NaOH and stirred for 24 hours. The organic phase was washed with water, and brine, dried over K2C0g and concentrated on a rotary evaporator. Chromatography on Florisil gave 178 mg. l-(l-ethoxymethyl)-4,5-bis (4-methoxyphenyl)-2-nitroimidazole as an oil. H—NMR:
. 1.08 δ (t, J=7H2,3H), 1.65 δ (d, J=6H2, 3H), 3.4 δ (q,J=7H,2H); 3.73 δ (S,3H), 3.86 δ (S,3H), 5.9 δ (q,
O=6H2,1H), 6.6—7.36 δ (2AB quartets, 8H), MS 352 (M—0C2H5), 325 (M—C2H30C2H5).
489 35
-28Other compounds that can be prepared by using the appropriate starting materials and the procedures described in the examples and in the Synthesis section are illustrated in the following table.
48835
TABLE 1 (continued)
^>—-F 4-N(CH3)2 Η H
.
Cl 4-OCHg H _CQ
4-0C2H5 H -COCHg
4-0C2H5 H
0CH3 3-C1
4-Cl
-ch2ogh2
488 35
V 48935
Dosage Forms.
The anti-arthritic and analgesic agents of this invention
. can be administered to treat arthritis and/or pain by any means that produces contact of the active agent with the agent’s site of action in the body of a mammal.
The compounds of formula 1 have anti-arthritic properties and in addition some can be used to alleviate pain. They
IQ. can be administered by any conventional means available for use in conjunction with pharmaceuticals; either as individual therapeutic agents or in a combination of therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on
. the basis of the chosen route of administration and standard pharmaceutical practice.
The dosage administered will, of course, vary depending upon known factors such as the pharmacodynamic characteristics of the particular agent, and its mode and route of administration; age, health, and weight of the recipient; g. nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, and the effect desired. Usually a daily dosage of active ingredient can be about 0.1 to 100 milligrams per kilogram of body weight. Ordinarily 0.1 to 50 and preferably 1.0 to 25 milligrams per kilogram
IQ. per day given in divided doses 2 to 4 times a day or in sustained release form is effective to obtain desired results.
Dosage forms (compositions)suitable for internal administration contain from about 1 milligram to about 500 milligrams of
. active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5—95% by weight based on the total weight of the composition.
The active ingredient can be administered orally in solid
. dosage forms, such as capsules, tablets, and powders, or in a liquid dosage forms, such as elixirs, syrups, and suspensions, it can also be administered parenterally in sterile liquid dosage forms.
-34Gelatin capsules contain the active ingredient and powdered carriers, such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stehrate, stearic acid, and the like. Similar diluents can be
. used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant
. taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
Liquid dosage forms for oral administration can contain coloring and flavoring to increase patient acceptance.
15i In general, water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions. Solutions for parenteral administration contain preferably a water
. soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, buffer substances. Antioxidizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid either alone or combined are suitable stabilizing agents. Also used are citric acid
. and its salts and sodium EDTA. In addition, parenteral solutions can contain preservatives, such as benzalkonium
-35chloride, methyl- or propyl-paraben,and chlorobutanol.
Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, E.W. Martin, a Standard reference text in this field.
. Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:Capsules
A large number of unit capsules are prepared by filling standard two-piece hard gelatin capsules each with 50 milligrams of powdered active ingredient, 175 milligrams of lactose, 24 milligrams of talc, and 6 milligrams magnesium stearate.
Capsules
. A mixture of active ingredient in soybean oil is prepared and injected by means of a positive displacement pump into gelatin to form soft gelatin capsules containing 50 milligrams of the active ingredient. The capsules are washed in petroleum ether and dried.
-36Tablets
A large number of tablets are prepared by conventional procedures so that the dosage unit is 50 milligrams of active ingredient, 6 milligrams of magnesium stearate, 70 milligrams of microcrystalline cellulose, 11 milligrams
. of cornstarch and 275 milligrams of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.
Injectable
A parenteral composition suitable for administration by
. injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water.
The solution is sterilized by filtration.
Suspension
An aqueous suspension is prepared for oral administration
. so that each 5 milliliters contain 10 milligrams of finely divided active ingredient, 200 milligrams of sodium carboxymethyl cellulose, 5 milligrams of sodium benzoate, 1.0 grams of sorbitol solution, U.S.P., and 0.025 milliliters of vanillin.
-37Injectable
A parenteral composition suitable for administration by injection is prepared by dissolving li by weight of active ingredient in sodium chloride injection U.S.P.
. XV and adjusting the pH of th'e solution to between 6 and
7. The solution is sterilized by filtration.
Use
To detect and compare the antiinflammatory activities of compounds in this series and standard drugs, a test was
, used based on a standard model of arthritis for which there is good correlation with human efficacy. The model is adjuvant-induced arthritis in rats. Federation Proceedings. Vo.. 32, No. 2 1973 Models Used for the Study and Therapy of Rheumatoid Arthritis -- Symposium ]g. of the American Society for Pharmacology and Experimental therapeutics — states The rat polyarthritis produced by intradermal injection of a suspension of Mycobacterium tuberculosis in mineral oil (adjuvant) has been used extensively for the screening of drugs of potential use in rheumatoid arthritis.
48935 '
-38Established Adjuvant-Induced Arthritis in Rats.
Charles River Lewis male rats (130—150 grams) are injected subcutaneously in the plantar area of the right hind
. paw with 0.1 ml of adjuvant (Difco heat-killed, lyophilized Mycobacterium butyricum suspended in mineral oil 5 mg/ml). 20 Nonarthritic controls are injected with mineral oil. The animals are held for two weeks to allow development of arthritis. Paw volumes (uninjected, left
. hind paw) are measured and the adjuvant injected rats are culled and distributed to treatment groups of 10 of equal disease severity. Nonarthritic controls are distributed to two groups of 10. The rats are given oral doses of compound or PVA—Acacia (Polyvinyl Alcohol
. 1%, Gum acacia, U.S.P. 5%, Methylparaben 0.5%) (10 ml/kg) by gavage on that day and on the six following days. One day after the last dose the paw volumes (uninjected, left hind paw) are measured using a Ugo Basile Volume Differential Meter Model 7101.
Mean Paw Volume (ml)
Arthritis Control
Treatment Group
Mean Paw Volume (ml
Arthritic control
Mean paw volume (ml)
Mean paw volume (ml' non-arthritic contri
x 100
48835
-39% decrease from control Mean Paw Volume.
Dose-response regression lines of the percent decrease are plotted on semi-log paper by visual fit and the ED50% decrease from control paw volume is determined
. by inspection. Data for some of the compounds in this invention are summarized in Table 11.
Compounds from this series were also compared to indomethacin, phenylbutazone, ibuprofen, and aspirin.
TABLE
.
Chemical Example Number
. l
Indomethacin
Phenylbutazone
Ibuprofen
. Aspirin_
II
Established Adjuvant-Induced Arthritis in rats (A.A.)
A.A. ED50% mg/kg
0.6(1.3)
2.5
0.3
100
305
-40h
Phenylquinone Writing Test.
A standard procedure for detecting and comparing the analgesic activity of compounds in this series for which there is good correlation with human efficacy is the
. standard phenylquinone writhingtest modified from
Siegmund, et al., Proc. Soc. Exp. Biol. Med. 95, 729 (1957). A test compound suspended in 1% methylcellulose was given orally to fasted (17—21hours) female white mice,
—20 animals per double blind test. Aqueous (0.01%
. phenyl-p-benzoquinone) phenylquinone was injected intraperitoneaiiy at 24 minutes later using 0.20 ml per mouse. Commencing at 30 minutes after the oral administration of the test compound, the mice were observed for 10 minutes for a characteristic stretching or
. writhing syndrome which is indicative of pain induced by phenylquinone. The effective analgesic dose for 50% of the mice (ED50; was calculated by the moving average method of Thompson, W.R., Bact, Rev. 11,
115—145 (1947); also time of peak action was determined
. for many of the compounds. This data is summarized in Table 111.
-41TABLE III
Phenyl quinone Writhing Test
Chemi cal Example
. Number ED50*
59.(30) < 130 ♦Units are in mg/kg at 1/2 hour.
Claims (12)
1. A compound of the formula with the proviso at least one of Rq and Rg must be -43Y 1 is F, Cl, N(CH 3 ) 2 or C 1 -C 4 alkoxy; Y 2 is H,F,C1; Rg is H, -CHORg, 2-tetrahydropyranyl, 2-tetrahydrofuranyl, 0 0 0 -OoRy -1!κ 7 , -ikr, or -SOgAr; 5. Rg is H or methyl; Rg is C-|-C 3 alkyl, benzyl -CHgCHgOCHg or Ry is Ο·] -C 4 alkyl or benzyl; and Ar is 10, where Yg is H.F.Cl,Br,Cj-C 4 alkyl, C^-C^ alkoxy or nitro; or a pharmaceutically suitable acid addition salt thereof where at least one of R 1 and Rg is 3-pyridyl or where Y 1 is N(CH 3 ) 2 or a pharmaceutically suitable metal salt thereof where 5. Rj is H.
2. A compound of Claim 1 where and R^ are
3. A compound of claim 1 where R-| or R 2 is Y-] is F, Cl, or 0CH 3> and Y 2 =H. -454. A compound of claim 3 where Y is in the para-position.
4. 5. A compound of claim 1 where Rg is H,
5. 6. A compound of Claim 2 where Rj or R 2 is 5. 5.
6. 7. A compound of claim 4 where Y-j is F, Cl or OCH 3 ; Y 2 is H; and Rg is H.
7. 8. The compound of claim 1 where R-j and R 2 are both and Rg is H. -469. The compound of Claim 1 where and Rg are both and Rg is H.
8. 10. A pharmaceutical composition consisting of a suitable 5 pharmaceutical carrier and an effective antiinflammatory amount of a compound of claims 1-9.
9. 11. A method for preparation of a compound of claims 1-9 which comprises (a) nitrating a compound of the formula where Pr is a protecting group, and R-| and Rg are as previously defined to form a compound of the formula Ν (b) optionally alkylating, acylating or sulfonylating the product of (a).
10. 12. A compound of formula I substantially as described herein with reference to the Examples. 5
11. 13. A pharmaceutical composition comprising a compound of formula I substantially as described herein with reference to the Examples.
12. 14. A method of preparing a compound of formula I substantially as described herein with reference to the 10 Examples.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US93771578A | 1978-08-29 | 1978-08-29 | |
| US06/018,023 US4199592A (en) | 1978-08-29 | 1979-03-06 | Antiinflammatory 4,5-diaryl-2-nitroimidazoles |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE791643L IE791643L (en) | 1980-02-29 |
| IE48935B1 true IE48935B1 (en) | 1985-06-26 |
Family
ID=26690639
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE1643/79A IE48935B1 (en) | 1978-08-29 | 1979-08-29 | Antiinflammatory 4,5-diaryl-2-nitroimidazoles,method for their preparation and pharmaceutical composition containing them |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US4199592A (en) |
| EP (1) | EP0008755B1 (en) |
| AR (1) | AR222834A1 (en) |
| AU (1) | AU525866B2 (en) |
| CA (1) | CA1131229A (en) |
| DE (1) | DE2962568D1 (en) |
| DK (1) | DK281079A (en) |
| ES (1) | ES483700A1 (en) |
| FI (1) | FI69451C (en) |
| GR (1) | GR71198B (en) |
| IE (1) | IE48935B1 (en) |
| IL (1) | IL58123A (en) |
| MX (1) | MX6046E (en) |
| NO (1) | NO152215C (en) |
| PH (1) | PH14620A (en) |
| PT (1) | PT70128A (en) |
| YU (1) | YU209979A (en) |
Families Citing this family (46)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4348404A (en) * | 1980-07-21 | 1982-09-07 | E. I. Du Pont De Nemours And Company | Antiinflammatory 4,5-diaryl-α-polyfluoroalkyl-1H-imidazole-2-methanamines |
| US4462992A (en) * | 1982-02-08 | 1984-07-31 | Research Corporation | Nitroimidazole radiosensitizers for hypoxic tumor cells and compositions thereof |
| US4503065A (en) * | 1982-08-03 | 1985-03-05 | E. I. Du Pont De Nemours And Company | Antiinflammatory 4,5-diaryl 1-2-halo imidazoles |
| EP0117485A3 (en) * | 1983-02-28 | 1985-01-23 | F. HOFFMANN-LA ROCHE & CO. Aktiengesellschaft | Pyridine, pyrazine and pyrimidine derivatives and their use as fungicides |
| US4686231A (en) * | 1985-12-12 | 1987-08-11 | Smithkline Beckman Corporation | Inhibition of 5-lipoxygenase products |
| US4780470A (en) * | 1986-08-19 | 1988-10-25 | Smithkline Beckman Corporation | Inhibition of interleukin-1 by monocytes and/or macrophages |
| US5916891A (en) | 1992-01-13 | 1999-06-29 | Smithkline Beecham Corporation | Pyrimidinyl imidazoles |
| US5670527A (en) * | 1993-07-16 | 1997-09-23 | Smithkline Beecham Corporation | Pyridyl imidazole compounds and compositions |
| US5593992A (en) * | 1993-07-16 | 1997-01-14 | Smithkline Beecham Corporation | Compounds |
| US5593991A (en) * | 1993-07-16 | 1997-01-14 | Adams; Jerry L. | Imidazole compounds, use and process of making |
| US5739143A (en) * | 1995-06-07 | 1998-04-14 | Smithkline Beecham Corporation | Imidazole compounds and compositions |
| US5658903A (en) * | 1995-06-07 | 1997-08-19 | Smithkline Beecham Corporation | Imidazole compounds, compositions and use |
| US6369068B1 (en) | 1995-06-07 | 2002-04-09 | Smithkline Beecham Corporation | Amino substituted pyrimidine containing compounds |
| ZA9610687B (en) | 1995-12-22 | 1997-09-29 | Smithkline Beecham Corp | Novel synthesis. |
| US6046208A (en) * | 1996-01-11 | 2000-04-04 | Smithkline Beecham Corporation | Substituted imidazole compounds |
| HUP9902460A3 (en) * | 1996-01-11 | 2000-03-28 | Smithkline Beecham Corp | Novel substituted imidazole compounds, their use, method for their preparation and pharmaceutical compositions containing them |
| AP9700912A0 (en) | 1996-01-11 | 1997-01-31 | Smithkline Beecham Corp | Novel cycloalkyl substituted imidazoles |
| ZA97175B (en) * | 1996-01-11 | 1997-11-04 | Smithkline Beecham Corp | Novel substituted imidazole compounds. |
| JP2000507558A (en) * | 1996-03-25 | 2000-06-20 | スミスクライン・ビーチャム・コーポレイション | Novel treatment for CNS injury |
| EP0956018A4 (en) | 1996-08-21 | 2000-01-12 | Smithkline Beecham Corp | Imidazole compounds, compositions and use |
| US5929076A (en) * | 1997-01-10 | 1999-07-27 | Smithkline Beecham Corporation | Cycloalkyl substituted imidazoles |
| AU7966198A (en) | 1997-06-13 | 1998-12-30 | Smithkline Beecham Corporation | Novel pyrazole and pyrazoline substituted compounds |
| JP2002505690A (en) | 1997-06-19 | 2002-02-19 | スミスクライン・ビーチャム・コーポレイション | Novel aryloxypyrimidine-substituted imidazole compounds |
| TW517055B (en) | 1997-07-02 | 2003-01-11 | Smithkline Beecham Corp | Novel substituted imidazole compounds |
| WO1999001452A1 (en) | 1997-07-02 | 1999-01-14 | Smithkline Beecham Corporation | Novel cycloalkyl substituted imidazoles |
| US6562832B1 (en) | 1997-07-02 | 2003-05-13 | Smithkline Beecham Corporation | Substituted imidazole compounds |
| US6489325B1 (en) | 1998-07-01 | 2002-12-03 | Smithkline Beecham Corporation | Substituted imidazole compounds |
| US7301021B2 (en) * | 1997-07-02 | 2007-11-27 | Smithkline Beecham Corporation | Substituted imidazole compounds |
| WO1999017776A1 (en) | 1997-10-08 | 1999-04-15 | Smithkline Beecham Corporation | Novel cycloalkenyl substituted compounds |
| EP1027050B1 (en) * | 1997-10-27 | 2004-01-14 | Takeda Chemical Industries, Ltd. | 1,3-thiazoles as adenosine a3 receptor antagonists for the treatment of allergy, asthma and diabetes |
| AR017219A1 (en) | 1997-12-19 | 2001-08-22 | Smithkline Beecham Corp | IMIDAZOL DERIVATIVES 1,4,5 SUBSTITUTES, COMPOSITIONS THAT INCLUDE THEM, PROCEDURE FOR THE PREPARATION OF SUCH DERIVATIVES, USE OF DERIVATIVES TO MANUFACTURE OF A MEDICINAL PRODUCT |
| CN1548436A (en) | 1998-05-22 | 2004-11-24 | ʷ��˿�������ȳ�ķ����˾ | Novel 2-alkyl substituted imidazole compounds |
| US6858617B2 (en) | 1998-05-26 | 2005-02-22 | Smithkline Beecham Corporation | Substituted imidazole compounds |
| WO2000010563A1 (en) * | 1998-08-20 | 2000-03-02 | Smithkline Beecham Corporation | Novel substituted triazole compounds |
| ATE258055T1 (en) * | 1998-11-04 | 2004-02-15 | Smithkline Beecham Corp | PYRIDINE-4-YL OR PYRIMIDINE-4-YL SUBSTITUTED PYRAZINE |
| US6239279B1 (en) | 1998-12-16 | 2001-05-29 | Smithkline Beecham Corporation | Synthesis for 4-aryl-5-pyrimidine imidazole substituted derivatives |
| JP2003514899A (en) | 1999-11-23 | 2003-04-22 | スミスクライン・ビーチャム・コーポレイション | 3,4-Dihydro- (1H) -quinazolin-2-one compounds as CSBP / p38 kinase inhibitors |
| US6759410B1 (en) * | 1999-11-23 | 2004-07-06 | Smithline Beecham Corporation | 3,4-dihydro-(1H)-quinazolin-2-ones and their use as CSBP/p38 kinase inhibitors |
| AU1783201A (en) | 1999-11-23 | 2001-06-04 | Smithkline Beecham Corporation | 3,4-dihydro-(1h)quinazolin-2-one compounds as csbp/p38 kinase inhibitors |
| ES2249309T3 (en) | 1999-11-23 | 2006-04-01 | Smithkline Beecham Corp | COMPOUNDS OF 3,4-DIHIDRO- (1H) QUINAZOLIN-2-ONA AS INHIBITORS OF CSBP / P39 KINASA. |
| US7235551B2 (en) * | 2000-03-02 | 2007-06-26 | Smithkline Beecham Corporation | 1,5-disubstituted-3,4-dihydro-1h-pyrimido[4,5-d]pyrimidin-2-one compounds and their use in treating csbp/p38 kinase mediated diseases |
| JP4524072B2 (en) * | 2000-10-23 | 2010-08-11 | グラクソスミスクライン・リミテッド・ライアビリティ・カンパニー | New compounds |
| PE20061351A1 (en) * | 2005-03-25 | 2007-01-14 | Glaxo Group Ltd | 8H-PYRID [2,3-d] PYRIMIDIN-7-ONA 2,4,8-TRISUSTITUTED COMPOUNDS AS CSBP / RK / p38 KINASE INHIBITORS |
| KR20080002865A (en) * | 2005-03-25 | 2008-01-04 | 글락소 그룹 리미티드 | Process for preparing pyrido[2,3-d]pyrimidin-7-one and 3,4-dihydropyrimido[4,5-d]pyrimidin-2(1h)-one derivatives |
| MD4150C1 (en) * | 2011-10-11 | 2012-09-30 | Институт Химии Академии Наук Молдовы | Process for producing coordinative compounds of Co(II), Ni(II) and Zn(II) with 2-nitro-4,5-diphenylimidazole starting from 4,5-diphenylimidazole and nitrates of said metals |
| MD4178C1 (en) * | 2012-02-27 | 2013-02-28 | Институт Химии Академии Наук Молдовы | Process for producing 2-nitro-4,5-diphenylimidazole |
Family Cites Families (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL124627C (en) * | 1964-08-12 | |||
| IL26729A (en) * | 1965-10-21 | 1970-10-30 | Geigy Ag J R | 2-mercaptoimidazole derivatives and process for their preparation |
| US3651080A (en) * | 1969-11-07 | 1972-03-21 | Ciba Geigy Corp | Certain substituted 2-alkylmercaptoimidazole derivatives |
| US3707475A (en) * | 1970-11-16 | 1972-12-26 | Pfizer | Antiinflammatory imidazoles |
| US3901908A (en) * | 1970-12-28 | 1975-08-26 | Ciba Geigy Corp | 2-alkyl- and 2-cycloalkyl-4,5-bis-phenyl-imidazoles |
| US3929807A (en) * | 1971-05-10 | 1975-12-30 | Ciba Geigy Corp | 2-Substituted-4(5)-(aryl)-5(4)-(2,3 or -4-pyridyl)-imidazoles |
| DE2229248C3 (en) * | 1971-07-30 | 1980-03-27 | Gruppo Lepetit S.P.A., Mailand (Italien) | 5-Iminomethyl-2-nitroimidazoI derivatives and process for their preparation |
| US4182769A (en) * | 1977-02-09 | 1980-01-08 | E. I. Du Pont De Nemours And Company | Anti-inflammatory 1-substituted-4,5-diaryl-2-(substituted-thio) imidazoles and their corresponding sulfoxides and sulfones |
| DK16778A (en) * | 1977-02-09 | 1978-08-10 | Du Pont | IMIDAZOLE DERIVATIVES THEIR USES AND MANUFACTURE |
-
1979
- 1979-03-06 US US06/018,023 patent/US4199592A/en not_active Expired - Lifetime
- 1979-04-28 PH PH22970A patent/PH14620A/en unknown
- 1979-07-03 DK DK281079A patent/DK281079A/en not_active Application Discontinuation
- 1979-08-24 CA CA334,410A patent/CA1131229A/en not_active Expired
- 1979-08-25 DE DE7979103139T patent/DE2962568D1/en not_active Expired
- 1979-08-25 EP EP79103139A patent/EP0008755B1/en not_active Expired
- 1979-08-27 AR AR277867A patent/AR222834A1/en active
- 1979-08-28 PT PT70128A patent/PT70128A/en unknown
- 1979-08-28 NO NO792787A patent/NO152215C/en unknown
- 1979-08-28 AU AU50354/79A patent/AU525866B2/en not_active Ceased
- 1979-08-28 IL IL58123A patent/IL58123A/en unknown
- 1979-08-28 MX MX798353U patent/MX6046E/en unknown
- 1979-08-28 YU YU02099/79A patent/YU209979A/en unknown
- 1979-08-28 ES ES483700A patent/ES483700A1/en not_active Expired
- 1979-08-29 FI FI792683A patent/FI69451C/en not_active IP Right Cessation
- 1979-08-29 GR GR59931A patent/GR71198B/el unknown
- 1979-08-29 IE IE1643/79A patent/IE48935B1/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DK281079A (en) | 1980-03-01 |
| EP0008755B1 (en) | 1982-04-21 |
| YU209979A (en) | 1983-04-30 |
| AR222834A1 (en) | 1981-06-30 |
| NO792787L (en) | 1980-03-03 |
| PT70128A (en) | 1979-09-01 |
| DE2962568D1 (en) | 1982-06-03 |
| ES483700A1 (en) | 1980-09-01 |
| IE791643L (en) | 1980-02-29 |
| PH14620A (en) | 1981-10-12 |
| FI69451B (en) | 1985-10-31 |
| CA1131229A (en) | 1982-09-07 |
| NO152215C (en) | 1985-08-28 |
| IL58123A (en) | 1983-05-15 |
| AU5035479A (en) | 1980-03-06 |
| GR71198B (en) | 1983-04-11 |
| EP0008755A1 (en) | 1980-03-19 |
| IL58123A0 (en) | 1979-12-30 |
| MX6046E (en) | 1984-10-11 |
| FI792683A (en) | 1980-03-01 |
| FI69451C (en) | 1986-02-10 |
| US4199592A (en) | 1980-04-22 |
| NO152215B (en) | 1985-05-13 |
| AU525866B2 (en) | 1982-12-02 |
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